DNA is continuously exposed to exogenous and genotoxic insults including ionizing and ultraviolet radiation as well as chemical agents. DNA damage can compromise the integrity of the genome and... Show moreDNA is continuously exposed to exogenous and genotoxic insults including ionizing and ultraviolet radiation as well as chemical agents. DNA damage can compromise the integrity of the genome and have potentially deleterious effects. Ultraviolet light (UV) can induce the formation of helix distorting lesions such as 6-4 photoproducts (6-4PP) and cyclopyrimidine dimers (CPD). In humans, the nucleotide excision repair (NER) pathway is solely responsible for the repair of these lesions. A defect in NER can lead to extreme sun sensitivity and an elevated risk of developing skin cancer as observed in patients with the inherited disorder xeroderma pigmentosum. The work described in this thesis focuses on NER in human cells. Findings include: 1) UV-DDB stimulates the repair of photolesions, 2) UV-DDB binds to UV lesions independently of XPC suggesting it may have a role in chromatin priming, 3) the sealing of DNA nicks during NER are entirely on XRCC1-DNA ligase III_ complex in quiescent cells, 4) RPA couples NER mediated incision to DNA repair synthesis and ligation, 5) Arsenic induces its co-carcinogenic effects at least in part by disrupting the sealing of DNA nicks that arise during NER. Show less
